drug substance patents: fda guidance, protecting...
TRANSCRIPT
Drug Substance Patents: FDA Guidance,
Protecting Composition-of-Matter Patents,
Drafting Solid Form Claims
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WEDNESDAY, JULY 10, 2019
Presenting a 90-minute encore presentation featuring live Q&A
Eyal H. Barash, Member, Barash Law, Lafayette, Ind.
Dr. Steef Boerrigter, Senior Research Investigator, Materials Science, SSCI, West Lafayette, Ind.
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SSCI - AMRI
• Solid State Chemical Information
• Founded by Prof. Stephen Byrn, Purdue University, 1991
• Specializes in solid-state aspects in drug development
• ~100 employees
• West Lafayette, IN
• Division of Albany Molecular Research, Inc.
© 2017 Albany Molecular Research Inc.6
Analytical and
Solid State
Services
Polymorphism
7
Drug Molecules Tend to Crystallize
Aspirin Ibuprofen (Advil)
© 2017 Albany Molecular Research Inc.8
Polymorphism of “ROY”
2-(2-Nitroanalino)-5-Methyl-3-Thiophenecarbonitrile
Red – Orange – Yellow
depending on conformation
Crystals of different
polymorphs Form PO-13, March 2019
http://xlink.rsc.org/?DOI=C8CE01930D
9
© 2017 Albany Molecular Research Inc.
Most Can Crystallize into Different Structures: Polymorphism
Acetaminophen / Paracetamol (Tylenol)
Form I Form II Form III
10
© 2017 Albany Molecular Research Inc.
Most Can Crystallize into Different Structures: Solvates
Acetaminophen / Paracetamol (Tylenol)
Monohydrate Dihydrate
Trihydrate
Pyridine Solvate
11
Analytical and
Solid State
Services
Cocrystals
12
© 2017 Albany Molecular Research Inc.
Cocrystals
• paracetamol:citric acid cocrystal
• paracetamol:oxalic acid cocrystal
13
FDA Guidance on Co-crystals (2018)
https://www.fda.gov/downloads/Drugs/GuidanceComplianceReg
ulatoryInformation/Guidances/UCM281764.pdf
27-fold solubility enhancement to
pterostilbene; sustained over 5 hours
1:1 pterostilbene:caffeine co-crystal
Schultheiss et al, 2010
14
Drug Substance Patents: Leveraging FDA Guidance,
Protecting Composition of Matter Patents, Drafting Solid Form Claims
Eyal H. Barash, J.D.
www.ebarashlaw.com
www.ssci-inc.com
Disclaimer
These materials are public information and have been prepared solely for
educational purposes to contribute to the understanding of American
intellectual property law.
These materials reflect only the personal views of the authors and are not
individualized legal advice.
It is understood that each case is fact-specific, and that the appropriate
solution in any case will vary. Therefore, these materials may or may not be
relevant to any particular situation.
The presentation of these materials does not establish any form of attorney-
client relationship. While every attempt was made to insure that these
materials are accurate, errors or omissions may be contained therein, for
which any liability is disclaimed.
16
Solid Form Patents As Drug Substance Patents in the Orange Book
• Challenge• Many drug products are approved in the US with no or limited drug
substance patent protection
• For typical small-molecule exits for composition of matter assets, drug substance patents provide the greatest value. Why?• Drug referencing via ANDA walks into infringement
• Species claims least likely to be declared invalid as a general rule
• Valuable in deal making!
• Opportunity• Solid Form patents may be used to “reset” the composition of matter
clock
• Solid form patents (e.g., salt, cocrystal, and polymorphs) are listed as drug substance patents in the Orange Book
• They may be narrower than the “organic” chemical compound patent
17
Drug Substance Patents with Later-Expiring Solid Form Patents – 2015 Drug Approvals
(Not including HW extensions)
• Corlanor®• No organic chemistry DS patent protection
• Solid form protection to 2026
• Addyi®• No organic chemistry DS patent protection
• Solid form protection to 2022
• Entresto®• No organic chemistry DS patent protection
• Solid form protection to 2027
• Farydak®• Organic chemistry DS patent protection to 2021
• Solid form protection to 2028
• Zurampic® • Organic chemistry DS patent protection to 2025
• Solid form protection to 2032
18
Farxiga®
• NCE is dapagliflozinpropanediol
• Approved on January 8, 2014
• NCE Exclusivity until January 8, 2019
19
Farxiga®
Appl No Prod No Patent NoPatent
Expiration
Drug
Substance
Claim
Drug Product
Claim
Patent Use
Code
N202293 001 6414126 Oct 4, 2020 Y Y U - 493
N202293 001 6515117 Oct 4, 2020 Y Y U - 493
N202293 001 6936590 Oct 4, 2020 U - 493
N202293 001 7851502 Aug 19, 2028 Y
N202293 001 7919598 Dec 16, 2029 Y
N202293 001 8221786 Mar 21, 2028 Y
N202293 001 8361972 Mar 21, 2028 U - 493
N202293 001 8501698 Jun 20, 2027 Y U - 493
N202293 001 8685934 May 26, 2030 U - 1522
N202293 001 8716251 Mar 21, 2028 Y
N202293 001 9198925 Oct 4, 2020 U - 493
Patent Data
20
Composition of Matter Claims
From Label
Claim 1 of 7,919,598 – expires December 16, 2029 Claim 1 of 6,515,117 – expires October 4, 2020
21
• Polymorphs • Guidance for Industry: ANDAs:
Pharmaceutical Solid Polymorphism July 2007
• Salts• 2017 Draft Guidance – (recall
1999 Draft Guidance with nothing until 2017!))
• Cocrystals• Guidance of 2018
Regulatory Scheme at FDA
22
Polymorphs at FDA
• “Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.” (p. 2).
• “Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.” (p. 2).
23
Polymorphs and “Sameness” at FDA
• ANDA must contain reference to an active ingredient that is the “same as” that in the Reference Listed Drug (RLD)
• Polymorphs of a drug substance differ in solid-state structure, but not chemical structure.
• “[D]ifferences in drug substance polymorphic forms do not render drug substances different active ingredients for the purposes of ANDA approvals.” (p. 5).
24
Salts at FDA
• Draft 1999 Guidance on 505(b)(2) applications• “A 505(b)(2) application is one for
which one or more of the investigations relied upon by the applicant for approval ‘were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted’ (21 U.S.C. 355(b)(2)).” (p. 2).
• Example includes “An application for a change in an active ingredient such as a different salt, ester, complex, chelate, clathrate, racemate, or enantiomer of an active ingredient in a listed drug containing the same active moiety” (p. 5).
25
Salts at FDA – Not Same in 1999
• “Active Moiety” • ”’the molecule or ion, excluding those appended portions of the
molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance’ (21 CFR 314.108(a)).” (p. 11) (Emphasis Added).
• 21 CFR 314.3• “Pharmaceutical equivalents are drug products in identical dosage
forms and route(s) of administration that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, . . . that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates..” (Emphasis Added).
26
New Draft Guidance in 2017 (still in Draft Form)
• In regards to the 1999 Draft Guidance, see footnote 5 of the 2017 Guidance - “For more information on 505(b)(2) applications, see the draft guidance for industry Applications Covered by Section 505(b)(2). When final, this guidance will represent the FDA’s current thinking on this topic.”
• 2017 Guidance is silent on salts
• However, it does discuss “sameness” of active ingredients
• See Section B.2 at Page 8
27
New Draft Guidance in 2017 – Section B.2
• If active ingredient is not the “same”, then ANDA is inappropriate route. However, FDA has “broad discretion to determine what sameness means in a 505(b)(2) context
• “FDA specifically rejected the adoption of requirements that active ingredients ‘exhibit the same physical and chemical characteristics [as the RLD], that no additional residues or impurities can result from the different manufacture or synthesis process, and that the stereochemical characteristics and solid state forms of the drug have not been altered.’ Instead, FDA has adopted a more flexible approach.
• In some instances, current limitations of scientific understanding and technology may preclude approval of an ANDA with the data permitted for submission in an ANDA, including, for example, with respect to establishing active ingredient sameness of a given product. As scientific understanding and technology evolve, though, FDA may be able to receive, review, and approve ANDAs where it previously lacked the scientific basis to do so.
• In other words, no clear technical or scientific standards
28
Cocrystals?
• Many comments to the Draft version of the original FDA Guidance argued there is no functional difference between a cocrystal and a salt
• Based on the “complex” and “clathrate” language of the 505(b)(2) Guidance, many had proceeded under the belief that FDA would regulate cocrystals as salts
• FDA Guidance of 2013, therefore, came as a great surprise to the Industry
29
Cocrystal Guidance of 2013
• “Regulatory Classification of Pharmaceutical Co-Crystals” April 2013
• Co-crystals are to be treated as drug product intermediates with the coformers are viewed as excipients
• Data should be submitted confirming that the API and the “excipient” exist in neutral states and interact nonionically
• “Assurance that complete dissociation of the API from its excipient occurs prior to reaching the site of action for pharmacological activity.” (p. 3).
• Negative response from Industry
• Draft Guidance had more than 20 responses critical of the Guidance
30
Ramifications of 2013 Guidance
• Problems with Cocrystal as “Drug Product Intermediate” (same
as “in process material” as per footnote 7.)
• Makes what scientists would normally consider drug substance – “drug
product”
• Different rules, regulations and practices for making and processing
drug substance and drug product
• Typically done in different facilities
• Chilling effect on cocrystal development
31
Revisiting the Guidance - 2016
• In August of 2016, FDA replaced the 2013 Guidance with a Draft Guidance (now Final) where Cocrystals were viewed as “special case” of solvates where coformer is non-volatile
• Data to confirm co-crystal rather than salt still present
• Assurance that API dissociation occurs before reaching site of pharmacological activity which can generally be done with in an intro evaluation based on dissolution or solubility data (no reference to “excipient”)
• Cocrystal will be viewed similarly as a polymorph of the API and not a new API
32
Cocrystals – A European Approach
• EMA published a “Reflection Paper” on Cocrystals on 21 May 2015
• Cocrystals are viewed as multi-component crystals with solvates and
hydrates being a subclass and are considered drug substance
• Cocrystals and salts are viewed on a “continuum”
• “Cocrystals, hydrates and solvates will therefore be considered eligible
for generic applications in the same way as salts are. . . unless they
differ with respect to safety and/or efficacy.” (Page 6 of Paper).
• Note, EMA view on salts
• “The different salts. . . . of an active substance shall be considered to
be the same active substance, unless they differ significantly in
properties with regard to safety and/or efficacy.” (Page 3 of Paper).
33
Cocrystals and Patents
• Cocrystals as Drug Substance
• Drug substance patents with potential listing in the Orange Book
• Cocrystals as “Polymorphs”
• Bioequivalent polymorphs to the polymorph in the RLD may reference the RLD
• The potential cocrystal “design-around” space is much larger than the typical design-around single-component polymorph space
34
Examples of Cocrystals on the Market
• Entresto®• Sacubitril and valsartan
• Stelgatro®• Ertugliflozin and 5-oxo-proline
• Suglat® (Japan)• Ipragliflozin and L-proline
35
Example 1
• Compound X is on the market – there are two polymorphs Form I and II and Innovator has both forms covered – drug launch in 2016
• Generic does cocrystal screen and finds a succinic acid cocrystal.
• The succinic acid cocrystal not covered by polymorph patents
• The succinic acid cocrystal is bioequivalent so an ANDA is filed referencing Innovator’s data and is approved
• Generic launches product and files patent on the succinic acid cocrystal
• Nothing Innovator can do with its polymorph patents to stop Generic
36
Example 1A
• Generic 2 sees this and screens and finds fumaric acid cocrystal
• It files another ANDA on its cocrystal since its formulated product is also bioequivalent
• Innovator cannot stop this with its polymorph patent
• Generic 1 cannot stop this with its succinic acid cocrystal patent
• Generic 2 patents its fumaric acid cocrystal
37
Options
• Get a genus claim covering cocrystals
• A genus claim is valuable to protect against a design-around that can reference safety and efficacy data
• Valuable IP to both innovators and generics
• What are some ways to think about generic claiming?
38
EnablementIn re Wright, 999 F.2d 1557 (Fed. Cir. 1993)
• Patent claimed method of making vaccines directed against all RNA viruses.
• Single working example in application directed to a specific avian RNA virus.
• Court will not grant such broad claim scope in unpredictable art, no reasonable expectation of success for such an extrapolation.
• Thus, harder to get a broad claim in an unpredictable art – working examples become increasingly important.
• Solid forms are typically considered an unpredictable “art”
39
Example 1 - Succinic, Fumaric, Maleic
40
• Common Features:• All carboxylic acids
• All di-acids
• All four carbons
Sample Independent Claims
• A cocrystal of Compound X and a coformer
• A cocrystal of Compound X and an organic acid coformer
• A cocrystal of Compound X and an organic diacid coformer
• A cocrystal of Compound X and a four-carbon organic acid coformer
• A cocrystal of Compound X and a coformer selected from the group consisting of succinic acid, fumaric acid, and maleic acid.
• Crystalline X: coformer (etc.)
41
Cocrystal X:_ Patent Claiming
Polymorphs I, II and
III
Maleic
Cocrystal
(1:1)
Fumaric
Cocrystal
(1:1)
Cocrystal Genus
42
Succinic
Cocrystal
(1:1)
I
II
II
I
Succinic
Cocrystal
(2:1)
Genus Cocrystal Claims
• Multiple Cocrystals
• Was only a single cocrystal made in the screen or 5 or 6?
• Teaching multiple methods of making cocrystals
• Good claim and specification drafting
• Identifying trends (i.e., C4 carboxylic acids)
• Was a method used to “reduce” search space based on hydrogen-bonding interactions, for example
• What was valuable and what was not valuable?
• Consider including hydrates and solvates
43
Composition of Matter Claims
From Label
Claim 1 of 7,919,598 – expires December 16, 2029 Claim 1 of 6,515,117 – expires October 4, 2020
44
Solid Form Patent – 7,919,598
Claim 1 of 7,919,598 – expires December 16, 2029 Claims 4-7 of 7,919,598 – expires December 16, 2029
45
Data Claiming – How Solid Form Claims Differ from Chemical Structure Claims
U.S. Patent No. 9,353,090
46
Data Claiming – How Solid Form Claims Differ from Chemical Structure ClaimsCompare to U.S. Patent Number 9,314,525
• No good language exists to define crystalline forms to pharmaceutical scientists which is as robust and commonly accepted as organic nomenclature for covalently bound compounds
• Unit cells not a convenient way to discuss solid forms in Pharma
• So, we use data as a surrogate for nomenclature
• The quality, amount, and type of data are critical when patenting solid forms
47
Claims with Data Limitations(Single Peak Used to Prove Infringement)
48
Glaxo v. Novopharm110 F. 3d 1562(Fed. Cir. 1997)
"It is elementary patent law that all limitations are material. The single-peak analysis was thus insufficient because, as the district court correctly noted, in order to prove infringement Glaxo was required to establish the presence of each limitation of the asserted claims.” Id. at 1566
• Twenty-nine peaks
• Nineteen end in 0
• Several – OH stretches claimed
49
Inherency (Species of Novelty) the typical scenario
• Patent 1 contains 50 examples, including Example 10 which teaches a synthetic scheme and ends with a “white crystalline solid” but provides no analytical data
• Example 10 is carried forward into the clinic and is approved by the regulatory authorities
• A polymorph screen is later done and two forms are found, I and II and a patent is filed on those forms
• Is such a patent valid? Issue = what was the form of Example 10 in Patent 1?
• If it was Form II, then Form II not patentable even though nobody knew what form it was at the time Patent 1 was filed/issued!
• See Ex Parte Reguri, Appeal No. 2007-0313
50
Qualities of the Invention Cannot be Obvious
Aspirin Methyl Salicylate
Would Aspirin be obvious over Methyl Salicylate?
51
Ex Parte Aronhime Appeal 2009-003073(October 19, 2009)
• Representative Claim (linezolid)17. Crystalline Linezolid characterized by data selected from the group consisting of: an X-ray powder diffraction pattern having peaks at about 4.7, 15.7, and 21.7 ± 0.2 degrees 2 theta, an FTIR spectrum having peaks at about 3090, 1524, 1335, 1195, 1115, 1081, 940, 927, 802, and 752 cm-1 and an FTRaman spectrum having peaks at about 2957, 2859, 880,752 and 715 cm-1.
• Examiner finds claims obvious because:• Barbachyn teaches same chemical composition of linezolid,
having just a different arrangement or different molecular conformations
• Brittain teaches that “mere difference in physical property is well known conventional variation of the same pure substance (see Brittain p.1-2).” (p.11).
• Thus, in absence of a showing of unexpected results, the claimed Form X would be obvious
52
Ex Parte Aronhime Appeal 2009-003073(October 19, 2009)
• Board Reverses
• None of the references suggest crystalline Form X and when a specific polymorph is claimed, “the prior art must make obvious the specific form that is claimed if the claim is to be held unpatentable under § 103.” (p. 13).
• No such showing by Examiner and, therefore, “no basis exists to require Appellants to provide evidence of unexpected results for the claimed product.” (p.13).
• Examiner erred in finding “crystalline Form X linezolid to be obvious based on Barbachyn and Brittain.” (p. 14).
53
Sanofi-Synthelabo v. Apotex, Inc., 492 F.Supp.2d 353 (S.D.N.Y. 2007)
(affirmed on appeal)
Predictability and Salts:
I. Berge = "[T]here is no reliable way of predicting the influence of a particular salt species on the behavior of the parent compound." Id. at 374.
II. Forming "a crystalline salt is important for an orally administered drug such as clopidrogel" due to its affect on solubility. Id.
III. "The prior art teaches – and both parties' experts agreed and the Court finds – that whether a crystalline material will form. . . the type of crystalline material that will form, and the properties . . . are all unpredictable." Id.
54
In re Armodafanil939 F. Supp. 2d 456 (D. Del. 2013)
• Polymorphism is unpredictable
• Large number of experiments needed and non-linear dependence on experimental conditions
• Cannot predict how to make a specific polymorph or predict its properties
• No reasonable expectation of success in obtaining Form I
• See also Merck & Cie v. Watson Laboratories, Inc. 125 F. Supp. 3d 503 (D. Del. 2013) (rev’d on other grounds)
55
Grunenthal GMBH v. Alkem Labs. Ltd. (Fed. Cir. 2019)
• Form B prior art form of tapentadol HCl; patent at issue directed to Form A
• Prior art discloses methods of screening for polymorphs
• At trial, lower court found patent was not invalid for obviousness
• On appeal, affirmed. Byrn (founder of SSCI) was key prior art.
• Byrn teaches flowcharts for screening including varying temperature, concentration, agitation. pH, etc. to look for
polymorphs
• Dr. Bernstein testified that a POSA could manipulate these and other variables and still not find a new polymorph of
a compound.
• Alkem argued that “any polymorph screening of a sample of tapentadol hydrochloride would result in Form A either
in whole or in part because Form A is more stable at room temperature.”
• Ct: “Here, a POSA did not know, or have reason to know, that tapentadol hydrochloride is polymorphic. Nor could a POSA know, or have reason to know, how the multiple variables involved in conducting a polymorph screen would affect the recrystallization of tapentadol hydrochloride. Byrn does not provide any guidance as to how the different solvents, varying temperatures, rates of agitation, or other variables used in polymorph screenings should be manipulated to even determine whether polymorphism occurs”
• “Obvious to Try” Fares no better. Varying parameters until one arrives at a solution, where there is no guidance in the prior art (ie, no recognition Form A exists), does not meet this standard. No reasonable expectation of success.
• Note – “Our decision today does not rule out the possibility that polymorph patents could be found obvious” ---But not on this record.
56
Conclusion
• Solid Forms are increasingly being used to protect drug substance assets
• FDA has made the use of cocrystals more attractive by reclassifying as drug substance
• Cocrystals have the potential of creating more opportunities to find new and improved drug delivery properties than salts or single-component polymorphs
• Protecting solid forms may be more important than ever with cocrystals
• Inherency less problematic a priori with cocrystals than single-component polymorphs
• Non-obviousness advantageous to patentees today, but should always prepare for unexpected results as is the law in the EU
57
Thank You
58